Bipolar Disorder is a common, often severe mental illness. Family, twin, and adoption studies have demonstrated that genes are the major determinant of individual risk for the disorder, but as in other common disorders, the identification of these genes has proven to be a significant challenge. In collaboration with 10 academic centers across the United States, we have recruited a large sample of families in which at least 2 siblings suffer from bipolar disorder or related mood disorders. This is the largest sample ever to participate in a genetic study of bipolar disorder. All research participants have undergone a diagnostic interview and provided a blood sample for DNA analysis. Genetic linkage studies have been performed using molecular markers evenly spaced across all chromosomes. These studies suggest that regions on chromosomes 8, 6, 13, 17, 18, and 22, among others, may contain genes that contribute to bipolar disorder in these families. Ongoing work is aimed at identifying the actual genes involved. Single nucleotide polymorphisms are being used to identify small chromosomal regions that are overrepresented in people with bipolar disorder. This work has so far identified the genes on chromosome 13, 22, and 18 as the sites of genetic variation that increase risk for bipolar disorder in some people. Related basic research aims to characterize the ways in which single nucleotide polymorphisms vary in groups across populations. This research has shown that patterns of long-range variation tend to mirror short-range variation within the same chromosomal region, supporting earlier reports that such patterns tend to be driven by regional differences in recombination rates, and that the identification of haplotype blocks depends on several variables. Related collaborative projects are aimed at investigating genetic variation in genetic components of the hypothalamic-pituitary-adrenal axis, important in the stress response; and the genes encoding the serotonin transporter and TPH2, important components of the serotonin signaling pathway that may mediate risk for mood and anxiety disorders.